What’s another (kilo)gram?

Prior to my current post, I’d not given too much thought to scale up.  I suspect to the majority of early career synthetic chemists, “large-scale” is synonymous with breaking out the one-liter round bottom flask.  That’s pretty much the comfortable upper bound of what you can work with 1) on a benchtop; 2) with magnetic stirring; and 3) with a oil bath heat source.

Your efforts on this scale will yield somewhere in the ballpark of 100 grams of product, depending on formula weight and a slew of other variables.  And what’s more, purification and workup has now ventured into the realm of things that are no longer routine.  A one-liter reaction volume is going to require a rather large separatory funnel (as a side note, Chemglass sells them up to 22-L — good luck with that).  And unless your starting materials and product have wildly different silica affinities, you’re going to have quite a bit of fun trying to run a 100-gram flash column, so you’ll likely have to break it into a couple runs.

And that’s all great until you need to crank out a kilogram of material.  You can now forget about running things in round bottomed flasks (Chemglass also sells a 22-L round bottomed flask, a testament to the age-old adage “just because you can does not mean you should“).  You’re also not going to have much luck trying to fit a vessel that size onto a hot plate, so that rules out both magnetic stirring (which would be ineffective anyway) and conventional heating baths or mantles.

Things like efficient mixing and heat transfer — which we hand wave away at the gram-scale — start to matter quite a bit once you cross the kilogram threshold.  So you’re going to need a specialized, jacketed reactor, through which you can recirculate a heated (or cooled) thermal transfer media.  And because surface area to volume ratios are the way they are, the temperature gradient between the outside of the reactor and the inside can be pretty dramatic.  So you’ve really got to get things mixed well, which means you need motorized stirring and a decent sized impeller.

Next on your synthetic checklist is workup, which now takes an entire day in and of itself.  Pray you don’t need to purify anything chromatographically.  Your precipitation that required 10 ml of solvent X per ml solvent Y suddenly won’t fit in any container in the lab, save the 55-gallon waste drum.  I’m not ashamed to admit I’ve MacGyvered a workup involving a 5-gallon orange Home Depot paint bucket at a previous position.

All this, and I haven’t even touched on time yet.  Everything at the kilo-scale takes longer.  A reaction which you could comfortably set up in 20 minutes at the gram scale will take you all morning to get going.  And you’d best triple check your work here, as mistakes on this scale are costly.

Of course, the proper process chemists will scoff at the struggles of the kilo-scale.  Steel reactors replace glass, drum evaporators replace rotavaps, and somehow I doubt the tried and true paint bucket workup would pass cGMP muster.

NMR on the X-Files

I was watching the X-Files last night — because bing-watching 1990’s television is how I opt to spend my free time — when the show mentioned a particular analytical technique readers will be well familiar with: NMR.

One of the reasons I love this show so much is because the blatant pseudo-science presented has a glimmer of real science somewhere embedded in it.  Sure it’s fiction; but I’ve never seen them put up a structure containing a Texas carbon (and I’ve been looking!).

In last night’s episode, Special Agent Dana Scully shows her partner, Special Agent Fox Mulder, a “nuclear magnetic resonance spectra [sic].”  This then comes on screen for a couple seconds (click to embiggen):

Screen cap from The X-Files S4E19 “Synchrony”, approximately 14:30 into the episode

A Proton NMR spectrum indeed!  The protagonist explains the analyte in question is a drop of blood from a murder victim; that’s an awfully clean spectrum from such a complex source.  The compound we are looking at is an experimental super toxin which “catalytically” induces freezing — and subsequent death — in it victims.

Obviously, no such catalyst exists, but this is a real NMR spectrum of something.  The solvent appears to be deutero-chloroform spiked with TMS.  There’s an aromatic signal almost directly on top of the chloroform singlet.  It gets complicated in the 6.5-5.5 region with olefins aplenty.  A singlet at ~4.1 could belong to some kind of substituted anisole, or a chloromethyl group?  The doublet at 3.3 has me stumped.  My first guess would be methylene adjacent to NH, but alas, no NH proton visible.  Down around 2-1 ppm we have a mess of methyl groups and what looks like a t-butyl at 1.2 ppm.

I am awarding a bounty of 10 internet points to the commenter who can propose the most plausible structure for this spectrum.  For historical context, the episode was filmed in 1996-97 in Cambridge, MA using MIT for some of the shots.  So it’s a possibility that the spectrum was pulled from an MIT lab.

Bigger booms, through chemistry

The Klapötke group at LMU is marching relentlessly onward with their quest to find new and interesting ways to stick as many nitrogen atoms onto one molecule in as close proximity as (barely) possible for long enough to get NMR data.

You may remember the Klapötke group from Derek’s post over at ItP in the “Azidoazide Azide” issue of Things I Won’t Work With.  This is the group that would look at pentazole and think “Gee, I wonder if we could replace that proton with an azide…”  I’ve always thought this kind of work was pretty cool; most of these crazy nitrogen heterocycles are practically useless but they serve the important purpose of giving us a better understanding of the nature of chemical bonds at the margin of what is possible.

Klapötke et al is back with a published patent application that showed up on my scanner.  This time, they’ve taken a step back from the realm of the ridiculous and have prepared a reasonable looking energetic active ingredient: 3,3′-dinitro-5,5′-bis-triazole-1,1′-diol (and a couple bis salts thereof).

untitled
And that structure looks not at all unreasonable.  Sure, electron deficient triazoles aren’t the most stable, but that hydroxyl contributes some electron density back to the ring system.  Oxygen balance looks good.  Slightly under-oxidized, actually, which as a rule gives you a bit of stability back.

But enough with speculation, let’s take a look at the thermal and sensitivity data provided in the text.  In energetics, RDX is commonly used as a benchmark: it has good (not great) explosive performance, and it reasonably insensitive to impact, friction, and electrostatic discharge.  Interestingly, the application does not present characterization data on the parent diol, but instead offers three salts: dihydroxylammonium (MAD-X1), diguanidinium (MAD-X2), and di-triaminoguanidinium (MAD-X3).

And the lead compound, MAD-X1, outperforms RDX across the board: better sensitivity in all three metrics, high detonation velocity (9.3 km/s to RDX’s 8.7), greater crystal density, higher thermal decomposition onset, larger heat of formation, and lower detonation temperature.  As anyone who works in the field knows, it’s really hard to have it all; you can always increase you explosive performance… at the expense of sensitivity.  And vice versa.  But, as far as performance metrics go, MAD-X1 seems to pretty handily have a leg up on the competition.

Even the synthesis is pretty straightforward and uses decidedly non-exotic reagents.  First, oxalic acid is condensed with aminoguanidinium bicarbonate in concentrated HCl, then worked up under basic conditions, affording 3,3′-diamino-5,5′-bis-(1H-1,2,4-triazole) (“DABT”).  DABT is then oxidized to the bis-nitro derivative as the corresponding dihydrate, which is fantastic from a energetics processing standpoint.  Treatment with potassium peroxymonosulfate affords the anhydrous diol, which reacts subsequently with an ethanolic solution of hydroxylamine, which yields MAD-X1 in 44% overall yield over four steps.

synthesis of MADx1

While not as concise as the two-step Bachmann process, which yields RDX from hexamethylenetetramine in 57% overall yield on an industrial scale, Klapötke’s preparation of MAD-X1 appears scalable.  Namely, it dispenses with the wildly exothermic nitrolysis process used to make nitramines — if you’ve ever had the pleasure of performing such a reaction you’ll know it’s incredibly easy to end up with a runaway reaction and a resultant yield rapidly approaching zero.  Do that on a large scale, and you’ll have a pilot plant rapidly approaching low earth orbit.

Overall, I’m pretty impressed with this compound’s prep and apparent utility.  My main criticism is: how’s that alkoxide salt going to hold up in an environment where metals are present?  Namely, in a casing or shell.  If the the use of picric acid has taught us anything, it’s that acidic energetics tend to not play well with metals.  I’d love to see some followup formulation work addressing this issue.

Strain energy for days: an in silico study of xinghaiamine A

SeeArrOh (via Twitter) reminded me of something I’ve been wanting to check out since this paper surfaced.

The paper in question features a supposed natural product, named “xinghaiamine A,” with some pretty wonky bonding.  Readers at Just Like Cooking and In the Pipeline brought up some issues regarding the evidence for this compound’s existence.  And rightly so; there appears to be something off about the supplemental data¹.  But, ignoring the (very real) issues readers have brought up with the supporting info for this paper, just look at this structure:

Oh dear

One half of the proposed compound.

At first glance, there’s some serious strain going on in there.  I figured I’d take a look at what xinghaiamine A looks like in 3D-space.  Getting it to behave in Spartan was a challenge on its own.  Chiefly, that bicyclo[2.2.0]hexane system was quite problematic.  Initial geometry optimizations at the semi-empirical level of theory produced some odd results.  I ended up settling on MMFF geometry optimization, which gave me the reasonably acceptable structure shown below²:

MMFF geometry optimization

MMFF geometry optimization of the xinghaiamine A “monomer”

Check out that bowl-shaped aromatic system.  That thing is supposed to be planar.

Check out that torsion angle: 40 degrees!

A torsion angle of 40 degrees.  And how!

The next logical step is to figure out exactly how much strain energy is in this thing.  This was done by taking the MMFF optimized geometry of xinghaiamine A and using it as a starting point for Spartan’s “T1 thermochemical recipe.”³  The T1 recipe is a post-Hartree-Fock method which consists of:

  • A quick and dirty HF/6-31G* geometry optimization
  • MP2 single point energy calculation with expanded basis set

This set of calculations yielded a heat of formation for xinghaiamine A of 1098.65 kJ/mol

Now, if we break that C-C bond joining the acenaphthalene and the bicyclo[2.2.0]hexane systems, repeat the calculations, and compare the results we can get a pretty decent idea of how much strain energy this proposed structure contains:

That planar acenaphthalene system looks so much happpier

That planar acenaphthalene system looks so much happpier

The answer is: a lot.

Breaking that one bond liberates quite a bit of energy.  But that’s not what makes this structure so implausible.  No, as others have pointed out, some of the motifs in this molecule have never been seen in a natural product.  And if you’re going to propose something never-before-seen, you best have the evidence to back it up.

Which raises the question: did the authors think the chemistry community would look at that structure and collectively go “yup, looks good to me, moving on then”?


  1. Something that rhymes with “fata dabrication”
  2. Note: the published structure is a dimer.  I’ve modeled it as a monomer, with a methyl R-group for computational simplicity
  3. Not a shill for Spartan, I promise

The Tools of the Trade

Ever wonder what an organic chemistry lab looks like?  Well, wonder no more!  I put together this virtual tour of sorts for the curious.  I’m going to take you through the facilities and equipment used by those who do what I do.

Tools of the trade: a virtual tour of an organic chemistry lab

The first stop every morning is the same: I boot up my computer and check Twitter.  Twitter has become an immensely useful tool for staying on top of new chemical research and gathering opinions from other scientists.  Other bloggers often discuss new methods from recent publications, and combined with scanning the feeds of major chemistry journals, I can get a rapid grasp on what’s important today.

That, and cracking lame chemistry jokes.

Next, it’s time to head down to my hood, where I spend the majority of my time.  For the uninitiated, a fume hood is a cabinet that pulls in air, creating negative pressure in the area where I’m doing experiments.  The air is then run through the ventilation system, and safely vented outside the building.  This prevents such unpleasant happenings as me getting a face-full of toxic hydrogen fluoride gas, or tripping out on diethyl ether fumes.

Where the magic (read: science) happens

Where the magic (read: science) happens

You’ll also notice a bunch of stuff sitting around my fume hood.  Starting from the top left, we have shelves of reagents and some glassware I use very frequently.  Then there’s the long, glass tube running horizontally across the top of the hood.  That’s called a Schlenk line; one end is hooked up to an inert gas (nitrogen or argon) and the other end to a vacuum pump.  This allows me to remove air and atmospheric water from a reaction flask, and replace it with inert gas.  Some compounds are highly sensitive to air.  Continuing to the right, you’ll see some waste containers, and a number of solvent bottles containing chemicals I use so frequently it makes sense to keep a stock of them in my hood.  Doubling back to the left (foreground) you’ll see a couple of hot plates, which double as magnetic stirrers.  These allow precise control of reaction temperature.

Everything so far is something you’d find in pretty much any organic chemist’s workspace.  However, you may have noticed the large aluminium plate making up the counter of the hood.  Since I work with explosive material, it is critical that the risk of static discharge be eliminated.  Rubbing your feet on carpet and then touching the compounds I work with would be inadvisable, to put it lightly.  So, my entire workspace is electrically grounded, including the floor in front of the hood.

We work with compounds that are SUPPOSED to go boom.  Ideally not mid-experiment though.

We work with compounds that are SUPPOSED to go boom. Ideally not mid-experiment though.

Another component of my workspace somewhat unique to explosive operations is steel armor plating.  The sides and rear of my fume hood are surrounded by ¼” thick steel plates.  In the unfortunate event of an accidental detonation, any fragmentation would be restricted from adjacent labs and hallways.

Rotary Evaporators

Rotary Evaporators

Next to my work area are two rotary evaporators or “RotaVaps.”  These allow chemists to rapidly remove solvent from reaction mixtures, isolating the products of the reaction.  By placing the mixture under a vacuum and providing gentle heating, the solvent boils much more rapidly (and at a lower temperature) than it otherwise would.  A cold trap then cools the gaseous solvent, where it condenses into a liquid in an adjacent flask.  Since these RotaVaps are also used for explosive material, they are also armored, just like my hood.

Now let’s check out the bread and butter of any organic chemist: the most powerful tool in my structural determination arsenal.  I am, of course, talking about nuclear magnetic resonance spectroscopy (NMR).  NMR is used to analyze the number and chemical environment of certain active nuclei.  Most commonly analyzed is hydrogen, followed by carbon; fluorine, nitrogen, and phosphorous are also active, but much less commonly analyzed.  NMR allows chemists to rapidly determine whether or not a reaction has worked as intended, and to verify the structure of compounds.

Our nuclear magnetic resonance spectrometer, AKA my one true love.

Our nuclear magnetic resonance spectrometer, AKA my one true love.

As always, thanks for reading!  Feel free to let me know how you felt about this piece, comments, questions, and suggestions are always welcome!

-Mitch

Safety First!

Safety First!

More on “You are what you eat”

Sense About Science recently posted a “public awareness” guide that hammers home a few of the points I made back when I wrote about chemicals in your food (PDF here).

The long and short of it: chemistry doesn’t need to be scary.

To quote the article:

The chemical reality is that you cannot lead a chemical-free life, because everything is made of chemicals. […] There are no alternatives to chemicals, just choices about which chemicals to use and how they are made.

 

It goes on to nicely summarize what chemists have been saying since the inception of chemical synthesis:

The chemical reality is that whether a substance is manufactured by people, copied from nature, or extracted directly from nature, tells us nothing much at all about its properties.

 

Give the article a read, and let’s put this whole all-natural obsession to rest for good.

Cheers,

Mitch

You Are What You Eat

This one’s for all you foodies out there.  The average American consumes somewhere around 2700 calories every day [1].  To put that number in perspective, a human consumes enough food energy to power a 100 Watt light bulb.  A family of four could power a desktop computer.  Your body functions by taking the chemical energy stored in the bonds of saccharides, proteins, and lipids (fats) and converting it into mechanical energy through a process called metabolism.  Micronutrients, such as vitamins and metal ions (iron, cobalt, sodium) are also introduced to the body through metabolic processes.

But not only does the body get much needed nutrients through eating, harmful substances can also be introduced in this way.  Toxic heavy metals can be introduced through contaminated ground water, or even fish.  Carcinogens, such as polycyclic aromatic hydrocarbons and dicarbonyls, can be found in cooked meats and liquors, respectively [2].

With that in mind, let’s examine some of the hazardous chemical compounds you didn’t know where in many of the foods you consume daily.

(2E)-3-phenylprop-2-enal

img1

Where it’s found: desserts, breads, baked goods, some perfumes, used as insecticide [7]

What it does: (2E)-3-phenylprop-2-enal is a skin and respiratory irritant.  In high enough doses, this compound is acutely toxic [3].

(9Z)-Octadec-9-enoic acid

img2

Where it’s found: most meats, including chicken, turkey, and beef, peanuts, and olives

What it does: In the blood stream, (9Z)-Octadec-9-enoic acid has been shown to induce severe respiratory failure and subsequent death by pulmonary edema in sheep [4].  It has furthermore been associated with increased incidence of breast cancer [5].

1,3,7-Trimethyl-1H-purine-2,6(3H,7H)-dione

img3

Where it’s found: many over the counter pain relievers and decongestants (Excedrin, DayQuil, others), chocolate, soda, tea, and coffee

What it does: First and foremost, 1,3,7-Trimethyl-1H-purine-2,6(3H,7H)-dione is teratogenic and mutagenic [6].  It is addictive and frequent consumption causes rapid physical dependence.  Furthermore, it is acutely toxic at certain doses, causing death by cardiac arrest.

8-Methyl-N-vanillyl-trans-6-nonenamide

img4

Where it’s found: fruits of plants belonging to the Capsicum genus, including bell peppers and jalapenos, paprika

What it does: In the laboratory, 8-Methyl-N-vanillyl-trans-6-nonenamide is classified as a hazardous material and requires the use of a respirator for safe handling.  Contact with skin or eyes results in severe irritation and burning, accompanied by local swelling.  Inhalation results in respiratory tract irritation.  It is acutely toxic in sufficient doses, and may have neurotoxic effects [8].

I Have a Confession to Make…

Up to this point, this entire article has been quite deceptive.  Intentionally so.  But I wrote it that way for a good reason, I promise.  Time for a quick poll: how many of you Google’d any of the compounds I just listed?  If you did, you would have found that I gave the systematic IUPAC names for quite common chemicals.

  • (2E)-3-phenylprop-2-enal is more commonly referred to cinnamaldehyde, and is the chief favorant in cinnamon.  Pure cinnamaldehyde, isolated from the essential oil of cinnamon tree bark, is a skin irritant; however, the cinnamaldehyde content in ground cinnamon is low enough for this to be a non-issue.  Furthermore, while it is technically toxic, the amount you would need to eat for negative effects to occur is huge – about half a pound for a healthy adult.
  • (9Z)-Octadec-9-enoic acid might be more recognizable as oleic acid, and makes up about 60% by mass of olive and canola oils.  It’s a very common fatty acid, usually found as a triglyceride in animal fat and many seeds and nuts.  Consumption of such monounsaturated fatty acids has been shown by trial after trial to have health benefits such as lower “bad” cholesterol.  While one study did show a link between high consumption of these fats and breast cancer, others have shown quite the opposite [9].  As for respiratory failure and pulmonary edema?  The researches induced these conditions in sheep intentionally by injecting pure oleic acid directly into their bloodstream.  So as long as you’re not shooting up olive oil, you should be alright there.
  • 1,3,7-Trimethyl-1H-purine-2,6(3H,7H)-dione might wake you up every morning, you probably just call it caffeine.  It is in fact mutagenic, hence why expectant mothers are instructed to avoid it.  However, the study demonstrating these properties in rats used injections of caffeine equivalent to a human dose of 100 cups of coffee.  This amount is incidentally very close to the median lethal dose in humans, which would of course be impossible to achieve by drinking coffee alone [10].
  • 8-Methyl-N-vanillyl-trans-6-nonenamide is what gives your chili its kick, but you most likely know it as capsaicin.  It’s in every chili pepper you cook with, from serranos to jalapenos to those absurd Indian ghost peppers.  Of course it’s an irritant, ever rubbed your eyes after eating something spicy?  The pure stuff, extracted and isolated from the peppers, is just much, much more potent.

So What’s the Point Here?

There seems to be some sort of pervasive fear of chemistry in society.  To a degree, I understand it; the 1950’s, gung-ho blind devotion to “Better Living Through Chemistry” brought us thalidomide and agent orange.  Carelessness brought us the tragic Bhopal incident in 1984.  It seems as though in a number of ways, chemical research has changed from “this is useful” to “this is dangerous” in the mind of the public.  I seldom go two days without seeing a link to some blog touting the horrors of synthetic food additives, GMO foods, or fluoride in the water.  The repeated chanting of “synthetic is bad, natural is good” ignores the fact that chemistry itself is indifferent.  I could just as easily have written this article from the opposite perspective: “All-Natural Drugs Found in Food.”  Hydrogen cyanide in Yuca plants, coniine in the hemlock bush, and amanitin in Amanita mushrooms, all of which are natural but deadly.

All science, let alone chemistry, requires a certain level of skepticism, without which true objectivity would be impossible.  A double-dose of skepticism may be necessary when dealing with things you ultimately put in your body.  With that being said, I hope the take-home message from this article is simply “think critically.”  Remember, any Joe (myself included) with some free time and $20 can set up a website and say whatever they want.  There is a vast amount of wonderfully useful information out there.  Unfortunately, there is also a huge quantity of misinformation mixed in with it.  As the 16th century German physician Paracelsus said, “All things are poison, and nothing is without poison; only the dose permits something not to be poisonous.”

Cheers,

Mitchell

P.S. This post is a bit different from what I usually publish, so as always, I welcome feedback.  Leave me a comment or shoot me an email (mtantalek@gmail.com).  I’m also interested in hearing what you would like to read about in future posts.

Sources:

  1. http://www.usda.gov/factbook/chapter2.pdf
  2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2379645/pdf/canfamphys00111-0173.pdf
  3. http://www.ncbi.nlm.nih.gov/pubmed/10866983
  4. http://jap.physiology.org/content/60/2/433.long
  5. http://jnci.oxfordjournals.org/content/93/14/1088
  6. http://onlinelibrary.wiley.com/doi/10.1002/tera.1420080109/abstract
  7. http://pubs.acs.org/doi/abs/10.1021/jf0497152
  8. http://www.sciencelab.com/msds.php?msdsId=9923296
  9. http://onlinelibrary.wiley.com/doi/10.1002/ijc.2910580604/abstract
  10. http://onlinelibrary.wiley.com/doi/10.1002/j.1552-4604.1967.tb00034.x/abstract